P1538: INHIBITION OF COMPLEMENT C1S WITH SUTIMLIMAB IN PATIENTS WITH COLD AGGLUTININ DISEASE (CAD): RESULTS FOLLOWING 9-WEEK WASHOUT PERIOD IN PHASE 3 CARDINAL STUDY (NCT03347396)
Authors: A. Röth, W. Barcellini, S. D’Sa, Y. Miyakawa, C. M. Broome, M. Michel, D. J. Kuter, B. Jilma, T. H. A. Tvedt, I. C. Weitz, T. Sourdille, J. Wang, D. S. Vagge, K. Kralova, F. Shafer, M. Wardecki, M. Lee, S. Berentsen
Journal: HemaSphere (2022)

Background: CAD is a rare, chronic autoimmune hemolytic anemia characterized by classical complement pathway (CP)-mediated hemolysis. Sutimlimab is a first-in-class humanized monoclonal antibody and C1s inhibitor that selectively targets the classical CP while leaving lectin and alternative pathways intact. Aims: To report results from the 9-week follow-up visit after the last sutimlimab dose in the CARDINAL study. Methods: CARDINAL is a two-part, open-label, single-arm study. In Part A, sutimlimab was administered on Days 0 and 7, then biweekly through Week 25. Patients then entered a Part B open-label extension and received biweekly sutimlimab for up to 3 years (N=22). Upon completion of dosing, or if a patient terminated the study early, a follow-up visit was completed 9 weeks after administration of the last dose of sutimlimab. Efficacy measures included hemoglobin (Hb) levels, hemolytic markers (total bilirubin, lactate dehydrogenase [LDH] and reticulocyte count); quality of life was assessed using the FACIT-Fatigue Score; PK/PD markers included Wieslab CP and total C4; adverse event data were collected. Descriptive statistics, frequency, or percentage were used to analyze outcomes. Results: Of 22 patients who entered study Part B, 20 were assessed at the 9-week follow-up visit; 2 patients were not assessed due to death during the 9-week follow-up period. From baseline to last available on-treatment value, mean Hb improved to >12 g/dL, a mean (SD) change from baseline of 3.6 (2.19) g/dL (n=22); the mean (SD) Hb level at 9-week follow-up was 10.1 (1.6) g/dL (n=20), a decrease of 2.28 (1.8) g/dL from the last available on-treatment value (Figure 1). The mean levels of selected hemolytic markers (including bilirubin, LDH, reticulocytes), were decreased compared to baseline at the last available on-treatment time point, returning towards baseline 9 weeks after the last sutimlimab dose (Figure 1). The mean (SD) FACIT-Fatigue score increased from 32.4 (10.9) at baseline to 40.5 (9.3) at the last available on-treatment time point and returned to 34.1 (14.3) points at the 9-week follow-up (Figure 1). From Week 1, total C4 was consistently increased from baseline during treatment and returned towards baseline at the 9-week follow-up. The near-complete inhibition of CP activity observed throughout the treatment period was reversed at follow-up after discontinuation of sutimlimab. 45 treatment-emergent adverse events (TEAE) occurred after the last dose of sutimlimab in 11 patients. 10 of the 11 patients experienced TEAEs that were attributed to exacerbation of underlying CAD and included worsening of CAD in 3 patients, hemolysis in 1 patient, acrocyanosis in 2 patients, and anemia in 4 patients. 5 events were reported as serious TEAE (TESAE) in 3 patients, including 2 fatal events. TESAEs included: non-cardiac chest pain in 1 patient; acrocyanosis and fatal event of klebsiella pneumonia in 1 patient; and a femoral neck fracture and death due to CAD exacerbation (approximately 1.5 months after the last dose of sutimlimab) in 1 patient with complex medical history including myelodysplastic syndrome. Image:Summary/Conclusion: In the 9-week washout period following the final dose of sutimlimab, classical complement pathway inhibition was reversed, and hemolytic markers and fatigue scores approached pre-sutimlimab values. Most of the TEAEs were due to exacerbation of underlying CAD.